AU675918B2

AU675918B2 - Treatment of acne or of pseudofolliculitis barbae

Info

Publication number: AU675918B2
Application number: AU29060/92A
Authority: AU
Inventors: F. Eugene Harrington; Douglas Shander; Mary Claire Whitmore
Original assignee: Gillette Co LLC
Current assignee: Gillette Co LLC
Priority date: 1991-10-30
Filing date: 1992-10-28
Publication date: 1997-02-27
Anticipated expiration: 2012-10-28
Also published as: JPH07500606A; EP0610368A4; KR100264829B1; EP0610368A1; MX9206239A; WO1993008790A1; ES2125276T3; ATE174785T1; DE69228000T2; EP0610368B1; HUT70393A; JP3534751B2; ZA928345B; OA09920A; DK0610368T3; HU219949B1; CA2121484C; US5328686A; DE69228000D1; HU9401258D0

Abstract

Patients suffering from acne and/or pseudofolliculitis barbae are treated by applying to the skin of the patient an inhibitor of ornithine decarboxylase.

Description

OPI DATE 07/06/93 APPLN, ID 29060/92 llIII III iIII 11111111 II IJIIIjI AOJP DATE 05/08/93 PCT NUMBER PCT/US92/09128 AU9229060

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(51) International Patent Classification 5 (11) International Publication Number: WO 93/08790 A6K 7/15 Al (43) International Publication Date: 13 May 1993 (13.05.93) (21) International Application Number: PCT/US92/09128 (72) Inventors; and Inventors/Applicants (for US only) SHANDER, Douglas (22) International Filing Date: 28 October 1992 (28.10.92) [US/US]; 16112 Howard Landing Drive, Gaithersburg, MD 20878 HARRINGTON, Eugene (US/ US]; P.O. Box 200, 54 West Main Street, New Market, Priority data: MD 21774 WHITMORE, Mary, Claire [US/US]; 785,032 30 October 1991 (30.10.91) US 1 Vista Avenue, Lynchburg, VA 24503 (US).

(74) Agents: HANDELMAN, Joseph, H. et al.; Ladas Parry, Parent Application or Grant 26 West 61 Street, New york, NY 10023 (US).

(63) Related by Continuation US 785,032 (CON) Filed on 30 October 1991 (30.10.91) (81) Designated States: AT, AU, BB, BG, BR, CA, CH, CS, DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, NO, PL, RO, RU, SD, SE, UA, US, Eu- (71) Applicant (for all designated States except US): THE GIL- ropean patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, LETTE COMPANY [US/US]; Prudential Tower Build- IE, IT, LU, MC, NL, SE), OAPI patent (BF, BJ, CF, ing, Boston, MA 02199 CG, CI, CM, GA, GN, ML, MR, SN, TD, TG).

Published With international search report.

(54) Title: TREATMENT OF ACNE OR OF PSEUDOFOLLICULITIS BARBAE 14 a 'W (57) Abstract Patients suffering from acne and/or pseudofolliculitis barbae are treated by applying to the skin of the patient an inhibitor of ornithine decarboxylase.

WGY 93/08790 PCT/US92/09128 -1- 1 Treatment of Acne or of Pseudofolliculitis Barbae This invention relates to the treatment of acne and pseudofolliculitis barbae (PFB) by the topical application of compositions containing materials capable of inhibiting the action of the enzyme ornithine decarboxylase (ODC). In a preferred embodiment of this invention, such inhibitors are applied along with an antiandrogen or a retinoid.

Although the exact mechanisms leading to acne are not known, antiandrogens, retinoic acid, steroids and -antibiotics, inter alia have generally been proposed for its treatment, as described in U.S. Patent Nos. 4,139,638; 4,161,540; 4,191,775; 4,344,943; and West German OLS no.

2,840,144.

PFB relates to the removal of hair by shaving or plucking. It has been treated by procedures such as the use of electric clippers or depilatories for hair removal, or by topical treatment with tretinoin (Retin-A), benzoyl peroxide, chlorohydroxyquinoline, chloroalkylphenols, phospholipids in combination with wheat germ oil and vitamin E, alpha-hydroxy acids, salicylic acid in combination with glucocorticoids and sulfur as shown for example in U.S.

patents 4,228,163, 4,463,016; 4,525,344; 4,775,530; and 4,944,939; and in Klingmjan et al., Arch. Dermatol., vol.

107, 551-52 (1973).

Many of the treatments for PFB, and particularly for acne, produce such serious side effects that the treatment can be justified only in the most severe cases; other treatments are of limited effectiveness.

-la According to the present invention there is provided a process of treating patients suffering from pseudofolliculitis barbae which comprises applying to the skin of said patient a composition comprising an inhibitor of the enzyme ornithine decarboxylase in a non-toxic pharmacologically acceptable vehicle.

Also provided according to the present invention is a process of treating patients suffering from acne which comprises applying to the skin of said patient a composition comprising an inhibitor of the enzyme ornithine decarboxylase in a non-toxic pharmacologically acceptable vehicle, said inhibitor being 2-(difluoromethyl) -2,5-diaminopentanoic acid.

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4* i WO 3/08790 PCT/US92/09128 2 The compound 2-(difluoromethyl) ornithine (DFMO, 2acid) and other inhibitors of ornithine dicarboxylase have been proposed for use in treating cancer and certain non-malignant diseases such as erythroderma, psoriasis, and some forms of dermatitis, etc. as described in Splinter et al., Eur. J.

Cancer and Clin. Oncology, Vol. 22:I-E, 61-67 (1985); McCullough et al. J. Investig. Dermatology, Vol. 85, 518- 521 (1985); McCullough et al., J. Investig. Dermatology, Vol. 81, 388-392 (1983); Kousa et al., Acta Dermatovener (Stockholm) Vol. 62, 221-224 (1982); and U.S. Patent 4,207,315.

It has now been found that topical administration of a cytostatic nontoxic agent such as 2(difluoromethyl)-2.5diaminopentanoic acid (d-difluoromethylornithine, DFMO) which inhibits the activity of the enzyme ornithine decarboxylase can be used to effectively ameliorate or control acne and/or PFB in patients with minimal or no unwanted side effects. DFMO can be used in combination with a topically active sebosuppressive agent such as an antiandrogen or a retinoid to gain the benefits of such agents for the treatment. Among the preferred inhibitors of ornithine decarboxylase, in addition to DFMO, which can be used in the present invention, are alpha-ethynyl ornithine; 6-heptyne-2,5-diamine; and esters of fluoromethyldehydroornithine. In choosing ODC inhibitors for use in the practice of the present invention it is important to avoid those having undesirable secondary pharmacological effects such as 5-hexyne-1,4-diamine. The inhibitors of ornithine decarboxylase are employed by dissolving or dispersing them in a conventional non-toxic pharmacologically acceptable vehicle or carrier VWAch may be in the form of a lotion, cream, salve, ointment, or stick IWO 3/08790 PCT/US92/09128 3 composition; while the precise concentration of inhibitor in vehicle or carrier is not critical it is generally desired that the composition contain from 1 to 20% of inhibitor by weight so that it can be applied to the affected areas of the skin of patients suffering from acne or PFB, particularly to the pimples or inflamed areas of the skin, at the rate of 40 to 800 micrograms per square centimeter.

The composition is preferably applied only to the pustules, vacuoles or inflamed areas of the skin although application to adjacent areas need not be avoided.

Among the antiandrogens which can be used along with the ODC inhibitor are cyproterone acetate, chlormadinone acetate, 17-alpha-propyltestosterone, 17-alphaallyitestosterone, a-a-a-trifluoro-2-methyl-4'-nitro-mpropionotoluidide, 6a-bromo-173-hydroxy-17a-methyl-4-oxa- 5a-androstane-3-one, 178-acetoxy-4a,5cyclo-A-homo-B-nor-5aandrost-l-ene-3-one, and spironolactone. For minimal alterations of other androgen-mediated bodily functions through systemic action, 17-alpha-propyltestosterone or 17alpha-allyltestosterone are preferred.

The following examples will serve to illustrate further the nature of the invention without acting as a limitation upon its scope.

EXAMPLL1 Ten women suffering'from mild to moderately severe grades of acne treated themselves twice daily over a 6 month period with an aqueous based vehicle (68% water, 16% ethanol, 5% propylene glycol, 5% dipropylene glycol, 4% benzoyl alcohol, and 2% propylene carbonate) containing of DFMO per 100 ml of the total composition. Dermatological observations were recorded by a dermatologist who noted skin conditions prior to treatment, at 12 and 24 weeks of treatment, and 12 weeks after withdrawal of treatment.

WO 93/08790 PCT/US92/09128 4 Of the ten women on treatment nine showed significant improvement in their acne condition. Of the nine who responded, four demonstrated complete resolution of acne within 12 weeks, and a fifth subject, for whom no 12 week observation was available, exhibited complete clearance by the 24th week. The four subjects in which acne was not completely cleared demonstrated progressively marked improvements through the course of treatment. After cessation of treatment at twelve weeks, continued observations were made on the nine of the original subjects including the eight who responded to treatment.

This post treatment follow up revealed that seven of eight exhibited a recurrence of acne after withdrawal of treatment. The total clearance or marked improvement in acne in 9 of 10 subjects after treatment with elfluornithine and its recurrence after treatment cessation demonstrates the efficacy of DFMO.

EXAMPLE 2 Nine women suffering from pseudofolliculitis treated themselves and were evaluated as described in Exampl' 1.

Five exhibited complete clearance, four of whom cleared within 12 weeks. Four additional women showed progressive improvements during 24 weeks of treatment. Of the nine women with pseudofoliculitis six were women from the group of 10 in Example 1 who suffered from acne as well. In the six women with both acne and PFB, three demonstrated complete clearing of both conditions and the other three exhibited substantial clearing of both conditions.

Claims

2. The process as claimed in claim 1, in which said inhibitor is 2-(difluoromethy1)-2 ,5-diamlinopentanoic acid.
3. The process of treating patients suffering from acne which comprises applying to the skin of said patient a composition comprising an inhibitor of the enzyme ornithine deparboxylase in a non-toxic pharmacologically acceptable vehicle, said inhibitor being 2-(difluoromethyl)-2,5-diaminopentanolc acid, :7::tret4n An Inhibitor of the enzyme ornithine decarboxylase when used for traiga patient suffering from pseudofolliculitis barbae by topical application. An inhibitor according to claimn 4, in which said Inhibitor is 2- s (dlfluoromethyl)-2,5-diaminopentanoic acid. tra~g6. An Inhibitor of the enzyrne ornithine decarboxylase when used for traiga patient suffering from acne by topical administration, said inhibitor being 2- (difluoromethyl)-2 ,5-diaminopentanolc acid. 20 DATED this Tv-entieth Day of January 1997 The Gillette Company Patent Attorneys for the Applicant SPRTJSON FERGUSON [N:ALI~o10I135:CMS 98sT'qt9 wosfl)64 'S HOSnW~S W890:20 2.6t E@ 14df INTERNATIONAL SEARCH REPORT F International application No. P CT1US92109128 A. CLASSMFCATrION OF SUBJECT MATTER IPC(S) :A61K 7/15 US CL :424M7; 514/844, 859, 887 According to Inuenatonal Patent Clsasification or to both national classification and IPC H. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. :424M7; 514/844, 859, 887 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data bas and, where pmcucable, search terms used) C. DOCUMENTS CONSIDERED TO HE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y US, A, 4,720,489 (SHANDER) 19 JANUARY 1988 1-7 See column 1, line 14 to column 2, line 6. Column 3, lines 5-36. Column 4, lines 17-30. Y US, A. 4,207,315 (VOORHEES ET AL.) 1-7 JUNE 1980. See column 1, Lines 22-39. Further documents are listed in the continuation of Box C. ED See patent family annex. Specalcsn of cited docin: -r ion doocmat pubLiso d o atht todonsmc ineilia dams or priority dde and at i ia lwit the WpB~tdm bt cited lo undershwd tio docdniogn dw gmeri a" of th" at Which ist ~cocmaeu princil or dwory uodcrtyas the k'iadan to be pan of paziiuha mietiam E' a~iu ocwma ubW~ r docmmzas of parbcdw rieaus the csiamed avendoa cw" be uiir doumet pbWW n o aftr te igcr Ongdewcowiend siovel or cmot be comiered to invaive in kyeadn Mop *L doosaat whic way throw doub an prior*t ckia~s) at which is w= the docianma n xaaaone cited .to mtabIth the puibLicatioa dame of mnother caeion or other dmmo aa~rMNztecsge vno s b spciWcomaiuini to itvols us airwaiv m" whom the dociuamL it .0 docet~ rfarng to an on! dieclomrs. ime. exhibitoti or od-e combiaed wh ame or more odher mit dornm. mach camb-0-o CDWbrag obviotsa oa puson *e ish the an doma pubtithed prior to the i ma filing daw hbut kwt tha donar ame of he mm git aMilY the priority dae chkea Date of the actual completion of the international starch Daue of mailing of the international search report 07 DECEMBER 1992 26 FEB 19 Name and mailing address of the ISA/ Authorized office ComuissIoner of Patiots and Trademarks Box Pc DA ESM.S.A Wshington, D..20231 JMSM ?A Facsimile No. NOT APPLICABLE Telephone No. (703) 308-2351 Form PCT/ISA/210 (second shetX)July 1992)* I.* JNTERNATIONAL SEARCH REPORT International application No, PCT/US91211 Box I Observtioin where certain claims were found unsearchable (Continum on of item I of first sheet) This inerstalm rqxort tt not been established in rexpect of ceutsin claims w-der Articic 17(2)(a) for the Wolowing reasons: 1. [E Claim Not.: 9 snd because they relate to subject matter not required to be searched by this Authority, natmely: Recitation of thc new use pertains to subject matter considered to be non-atawutoy by this authority since no method steps have been recited. Use claims must be in method termiinology. 2.D because the; relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. CL,-i=aNot.: because they are dependat claims and ame not drafted in accorda=c with the second and third satencs of Rule 6.4(a). Box If Observations where unity of invention is Lackingt (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2.7 As all searchable clale'm could be searched without effort justifying an additional fee, this Authority did not invite payment of any addtional fee. 3. As only some of the reqiirod additional sech fees were timely paid by the appliant, this international search report covers only those claim for which fees were paid, specifically claims Nos.:
4. DNo required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention frist mentioned in the claims; it is covered by claim Nos.: Remark on Protest E Th additional search fees were accompanied by t applicant's protes. E No protes accompanied the payment of additional search fees. Form PCT/lSA/210 (continuation of first sheet(l))XJuly 199)*